Deciding When to Submit a 510(k) for a Change to an Existing Device Draft Guidance for Industry and Food and Drug Administration Staff

Deciding When to Submit a 510(k) for a Change to an Existing Device Draft Guidance for Industry and Food and Drug Administration Staff DRAFT GUIDANCE This draft guidance document is being distributed for comment purposes only. Document issued on August 8, 2016. You should submit comments and suggestions regarding this draft document within 90 days of publication in the Federal Register of the notice announcing the availability of the draft guidance. Submit electronic comments to http://www.regulations.gov. Submit written comments to the Division of Dockets Management (HFA-305), Food and Drug Administration, 5630 Fishers Lane, rm. 1061, Rockville, MD 20852. Identify all comments with the docket number listed in the notice of availability that publishes in the Federal Register. For questions about this document regarding CDRH-regulated devices, contact the 510(k) Staff at 301-796-5640. For questions regarding the use or interpretation of this guidance in the review of submissions to the Center for Biologics Evaluation and Research, contact the Office of Communication, Outreach and Development at 1-800-835-4709 or 240-402-8010 or by email at ocod@fda.hhs.gov. When final, this document will supersede Deciding When to Submit a 510(k) for a Change to an Existing Device, dated January 10, 1997. U.S. Department of Health and Human Services Food and Drug Administration Center for Devices and Radiological Health Center for Biologics Evaluation and Research

Additional Copies Contains Nonbinding Recommendations Preface CDRH Additional copies are available from the Internet. You may also send an e-mail request to CDRH-Guidance@fda.hhs.gov to receive a copy of the guidance. Please use the document number 1500054 to identify the guidance you are requesting. CBER Additional copies are available from the Center for Biologics Evaluation and Research (CBER), by written request, Office of Communication, Outreach, and Development (OCOD), 10903 New Hampshire Ave., Bldg. 71, Room 3128, Silver Spring, MD 20993-0002, or by calling 1-800-835-4709 or 240-402-8010, by email, ocod@fda.hhs.gov or from the Internet at http://www.fda.gov/biologicsbloodvaccines/guidancecomplianceregulatoryinformation/g uidances/default.htm.

Table of Contents 1. Introduction 1 2. Background 1 3. Scope 3 4. Guiding Principles 4 5. How to Use This Guidance 6 A. Labeling Changes 11 B. Technology, Engineering, and Performance Changes 18 C. Materials Changes 27 D. Technology, Engineering, Performance, and Materials Changes for In Vitro Diagnostic Devices 31 E. Considerations for Risk Assessments of Modified Devices 36 Appendix A: Examples 39 Appendix B: Documentation 58 Appendix C: Definitions 69 Flowcharts Figure 1 - Main Flowchart 8 Figure 2 - Flowchart A 12 Figure 3 - Flowchart B 19 Figure 4 - Flowchart C 28 Figure 5 - Flowchart D 32

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 Deciding When to Submit a 510(k) for a Change to an Existing Device Draft Guidance for Industry and Food and Drug Administration Staff This guidance, when finalized, will represent the current thinking of the Food and Drug Administration (FDA or Agency) on this topic. It does not establish any rights for any person and is not binding on FDA or the public. You can use an alternative approach if it satisfies the requirements of the applicable statutes and regulations. To discuss an alternative approach, contact the FDA staff responsible for this guidance as listed on the title page. 1. Introduction Almost from the enactment of the Medical Device Amendments to the Federal Food, Drug, and Cosmetic Act (the FD&C Act) in 1976, the Food and Drug Administration (FDA or the Agency) has attempted to define with greater clarity when a change in a medical device would trigger the requirement that a manufacturer submit a new premarket notification (510(k)) to the Agency. When finalized, this document will supersede Deciding When to Submit a 510(k) for a Change to an Existing Device (K97-1), issued on January 10, 1997. For the current edition of the FDA-recognized standards referenced in this document, see the FDA Recognized Consensus Standards Database at http://www.accessdata.fda.gov/scripts/cdrh/cfdocs/cfstandards/search.cfm. FDA s guidance documents, including this draft guidance, do not establish legally enforceable responsibilities. Instead, guidances describe the Agency s current thinking on a topic and should be viewed only as recommendations, unless specific regulatory or statutory requirements are cited. The use of the word should in Agency guidance means that something is suggested or recommended, but not required. 2. Background 1

36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 61 62 63 64 65 66 67 68 69 70 71 72 73 74 75 76 77 78 79 80 The regulatory criteria in 21 CFR 807.81(a)(3) state that a premarket notification must be submitted when: (3) The device is one that the person currently has in commercial distribution or is reintroducing into commercial distribution, but that is about to be significantly changed or modified in design, components, method of manufacture, or intended use. The following constitute significant changes or modifications that require a premarket notification: (i) A change or modification in the device that could significantly affect the safety or effectiveness of the device, e.g., a significant change or modification in design, material, chemical composition, energy source, or manufacturing process. (ii) A major change or modification in the intended use of the device. FDA issued the original Deciding When to Submit a 510(k) for a Change to an Existing Device (K97-1) on January 10, 1997 to provide guidance on this regulatory language. As stated in that guidance, the key issue regarding 21 CFR 807.81(a)(3) is that the phrase could significantly affect the safety or effectiveness of the device and the use of the adjectives "major" and "significant" sometimes lead FDA and device manufacturers to different interpretations. That guidance provided the Agency s interpretation of these terms, with principles and points for manufacturers to consider in analyzing how changes in devices may affect safety or effectiveness and determining whether a new 510(k) must be submitted for a particular type of change. This draft guidance preserves the basic format and content of the original, with updates to add clarity. The added clarity is intended to increase consistent interpretations of the guidance by FDA staff and manufacturers. The 510(k) Process and the Quality System Regulation Any guidance on 510(k)s for changes to a legally marketed device should consider the role the Quality System (QS) regulation, 21 CFR Part 820, plays in changes to devices. For some types of changes to a device, the Agency believes that a new 510(k) is not necessary and that reliance on existing QS requirements may reasonably assure the safety and effectiveness of the changed device. Among other requirements, the QS regulation requires manufacturers of finished medical devices to review and approve changes to device design and production (21 CFR 820.30 and 820.70) and document changes and approvals in the device master record (21 CFR 820.181). Any process whose results cannot be fully verified by subsequent inspection and testing must be validated (21 CFR 820.75), and changes to the process require review, evaluation, and revalidation of the process where appropriate (21 CFR 820.75(c)). The net effect of the QS regulation is to require that, when manufacturers of a finished medical device make a change in the design of a device, there is a process in place to 2

81 82 83 84 85 86 87 88 89 90 91 92 93 94 95 96 97 98 99 100 101 102 103 104 105 106 107 108 109 110 111 112 113 114 115 116 117 118 demonstrate that the manufactured device meets the change in design specifications (or the original specifications, if no change was intended). They must keep records, and these records must be made available to an FDA investigator (see Section 704(e) of the FD&C Act). For many types of changes to a device, a new 510(k) may not be required per 21 CFR 807.81(a)(3). In these cases, compliance with the QS regulation can reasonably assure the safety and effectiveness of the changed device. 3. Scope This guidance, when finalized, will aid manufacturers of medical devices subject to premarket notification requirements who intend to modify a 510(k)-cleared device or a preamendments device subject to 510(k) (also referred to together as existing devices ) during the process of deciding whether the modification exceeds the regulatory threshold of 21 CFR 807.81(a)(3) for submission and clearance of a new 510(k). Note that any person required to register under 21 CFR 807.20 who plans to introduce a device into commercial distribution for the first time must, per 21 CFR 807.81(a)(2), submit a 510(k) if that device is not exempt from premarket notification requirements. 1 This guidance, when finalized, is not intended to address modifications to devices that are 510(k)-exempt or require premarket approval (PMA). This document incorporates concepts and recommendations from existing FDA guidance and policy, such as Submission and Review of Sterility Information in Premarket Notification (510(k)) Submissions for Devices Labeled as Sterile, and device-specific guidance documents regarding when new 510(k)s are required based on modifications to an existing device. In some cases, FDA s thinking has derived from its experience in situations involving only a few manufacturers of a limited number of devices. In such instances, we have attempted to generalize the concepts to apply to a broader range of devices. However, special cases exist where FDA has established definitive guidance for modifications to specific devices, e.g., FDA s guidance on daily wear contact lenses, Premarket Notification (510(k)) Guidance Document for Daily Wear Contact Lenses. This guidance, when finalized, is not intended to supersede such device-specific guidance but may cover areas not addressed in such devicespecific guidance. Recalls: This guidance, when finalized, is also intended to apply to situations when a legally marketed existing device is the subject of a recall and a change in the device or its labeling is indicated. For more information on recommended procedures in a recall situation, please see Blue Book Memorandum K95-1, 510(k) Requirements During Firm-Initiated Recalls. As stated in that guidance, if a correction alters a device rather than simply restoring it to its original specifications, a new 510(k) may be required. This guidance, when finalized, may be 1 Also note that devices with changes requiring a new 510(k) may not be legally commercially distributed before FDA clears the changed device. See 21 CFR 801.100(a) and sections 513(f)(1) and 513(i) of the FD&C Act. 3

119 120 121 122 123 124 125 126 127 128 129 130 131 132 133 134 135 136 137 138 139 140 141 142 143 144 145 146 147 148 149 150 151 152 153 154 155 156 157 158 159 160 161 useful in determining whether a new 510(k) is warranted in cases where the correction does alter the device. Private Label Distributors and Repackagers: Private label distributors and repackagers are exempt from submitting a 510(k) if they satisfy the requirements of 21 CFR 807.85(b). Software Changes: This draft guidance does not apply to software changes or modifications, however, this guidance does apply to non-software changes to devices containing software or software that is a medical device on its own. Labeling changes to existing devices that contain or consist of software are covered by Section A of this guidance, and non-software technology changes and materials changes to existing devices that contain software are covered by Sections B through D of this guidance. FDA is issuing a separate draft guidance document on software changes or modifications concurrently with this draft guidance. Combination Products: This draft guidance does not specifically address combination products, such as drug/device or biologic/device combinations, however, the general principles and concepts described herein may be helpful to manufacturers in determining whether a 510(k) is necessary for changes to device constituent parts of combination products. Furthermore, this guidance, when finalized, is not intended to address whether 510(k) submissions are required from remanufacturers of existing devices who do not hold the 510(k) for the device, such as reprocessors of single-use devices. Remanufacturer is defined at 21 CFR 820.3(w) as any person who processes, conditions, renovates, repackages, restores, or does any other act to a finished device that significantly changes the finished device s performance or safety specifications, or intended use. 4. Guiding Principles In using this guidance for deciding whether to submit a new 510(k) for a modification to an existing device, a number of guiding principles should be followed. Some derive from existing FDA 510(k) policy and are widely known, and others are necessary for using the logic scheme contained in this guidance. Thus, anyone using this guidance should bear in mind the following guiding principles: Modifications made with intent to significantly affect safety or effectiveness of a device If a manufacturer modifies their device with the intent to significantly improve the safety or effectiveness of the device (for example, in response to a known risk, adverse events, etc.), a new 510(k) is likely required. Changes that are not intended to significantly affect the safety or effectiveness of a device, however, should still be evaluated to determine whether the change could significantly affect device safety or effectiveness. o If a manufacturer modifies their device to address a violation or recall, they should refer to FDA guidances Blue Book Memorandum K95-1, 510(k) 4

162 163 164 165 166 167 168 169 170 171 172 173 174 175 176 177 178 179 180 181 182 183 184 185 186 187 188 189 190 191 192 193 194 195 196 197 198 199 200 201 202 203 204 205 206 Requirements During Firm-Initiated Recalls and Distinguishing Medical Device Recalls from Medical Device Enhancements. Could significantly affect evaluation and the role of testing To determine whether a change or modification could significantly affect the safety or effectiveness of a device, the manufacturer should first conduct a risk-based assessment, using the guidance below, of whether the change could significantly affect the device s safety or effectiveness, either positively or negatively. This risk-based assessment should identify and analyze all new risks and changes in known risks resulting from the device modification, and lead to an initial decision whether or not a new 510(k) is required. If the initial decision following the risk assessment is that a new 510(k) is not required, this decision should be confirmed by successful, routine verification and validation activities. If routine verification and validation activities produce any unexpected issues, any prior decision that a new 510(k) is not required should be reconsidered, as discussed in B5.4 for non-ivd devices and D4 for IVD devices. Verification and validation requirements apply for all devices subject to 21 CFR 820.30. Unintended consequences of changes In evaluating whether a change requires a new 510(k), manufacturers should consider whether there are any unintended consequences or effects of the device change. For example, changes in sterilization may unintentionally affect device materials, or changes to materials may unintentionally affect the performance of the device. Use of risk management The risk profile referred to throughout this document is based on the combination of multiple risk concepts which are important for managing the risks of medical devices. Hazards and hazardous situations, risk estimation, risk acceptability, risk control, risk/benefit analysis and overall risk evaluation are all concepts that can be applied during the design and development of a medical device. The concept of risk, as defined in ISO 14971: Medical devices Application of risk management to medical devices, is the combination of the probability of occurrence of harm and the severity of that harm. Although the risk terminology used in this document is primarily derived from ISO 14971, it is recognized that an individual manufacturer s terminology may differ. Because 21 CFR 807.81(a)(3)(i) requires a new 510(k) when a change could significantly affect safety or effectiveness, both safety and effectiveness should be considered in evaluating a device s risk profile, as explained in Section E. Evaluating simultaneous changes Because many simultaneous changes may be considered at once, each change should be assessed separately, as well as in aggregate. Appropriate comparative device and cumulative effect of changes In using this guidance to help determine whether a particular change requires the submission of a new 510(k), manufacturers should make a risk-based assessment that compares the 5

207 208 209 210 211 212 213 214 215 216 217 218 219 220 221 222 223 224 225 226 227 228 229 230 231 232 233 234 235 236 237 238 239 240 241 242 243 244 245 246 247 248 249 changed device to their device as previously found to be substantially equivalent in their most recently cleared 510(k) (or to their preamendments device, if no 510(k) has been cleared). Manufacturers may make a number of changes without having to submit a new 510(k), but each time they make a change, the device they should compare it to is their most recently cleared device. When the manufacturer compares the proposed modified device to the device in its most recently cleared 510(k), the manufacturer should evaluate the cumulative impact of all changes since their most recently cleared 510(k). Documentation requirement Whenever manufacturers change their device, they must take certain actions to comply with the QS regulation, 21 CFR Part 820, unless the device in question is exempt by regulation from the QS regulation. The QS regulation requires, among other things, that device changes be documented (See Appendix B for recommendations on documentation). 510(k) submissions for modified devices When a new 510(k) is submitted for a device with multiple modifications, that 510(k) should describe all changes that trigger the requirement for a new 510(k). That 510(k) should also describe other modifications since the last cleared 510(k) (i.e., those that did not require a new 510(k)) that would have been documented as part of the original 510(k) for that device. This helps ensure that FDA has a more complete understanding of the device under review. For instance, an original 510(k) would not typically identify or describe individual components of a circuit board, such as resistors, and therefore FDA would not expect modifications to the resistors to be listed in the new 510(k) for a modified device if they did not trigger the requirement for a 510(k). However, 510(k)s typically include a listing of device warnings in the labeling, so if a warning in the device s labeling has been modified, that change should be described in the new 510(k) even if that change did not itself trigger the requirement for a new 510(k). o If a manufacturer makes multiple changes to a device, but only one change triggers the requirement for a new 510(k), the changes that do not require a new 510(k) may be immediately implemented, so long as those changes can be implemented independently of changes that do require a new 510(k). Those changes should, however, be described in the new 510(k) for the change that does require submission (subject to the preceding bullet). Substantial equivalence determinations Manufacturers should understand that, even though they may follow this guidance and submit a new 510(k), a substantially equivalent determination is not assured. See The 510(k) Program: Evaluating Substantial Equivalence in Premarket Notifications (510(k)) for more information on the decision-making process FDA uses to determine substantial equivalence. 5. How to Use This Guidance 6

250 251 252 253 254 255 256 257 258 259 260 261 262 263 264 265 266 267 268 269 270 271 272 This guidance uses flowcharts and text to guide manufacturers through the logic scheme we recommend to arrive at a decision on whether to submit a new 510(k) for a change to an existing device. A single logic scheme containing all the necessary steps would be large and cumbersome and could be quite daunting. Therefore, one is not included in this document. Rather, for ease of use, the single scheme has been broken down into smaller sections that include: The main types of changes that might be made to a device (this section, Main Flowchart) Labeling changes (Section A, Flowchart A) Technology, engineering, and performance changes (Section B, Flowchart B) Materials changes (Section C, Flowchart C) Technology, engineering, performance, and materials changes for in vitro diagnostic devices (IVDs) (Section D, Flowchart D) Considerations for risk assessments of modified devices (Section E) Note that sections B and C are only applicable to non-ivds, and section D is only applicable to IVDs. All other sections apply to IVDs and non-ivds alike. Please refer to Appendix C: Definitions, for the meaning of terms used in the guidance, including in the flowcharts. 7

273 274 Figure 1 - Main Flowchart 8

275 276 277 278 279 280 281 282 283 284 285 286 287 288 289 290 291 292 293 294 295 296 297 298 299 300 301 302 303 304 305 306 307 308 309 310 311 312 313 314 315 316 317 318 319 Manufacturers should use the flowcharts in concert with the guiding principles above, the recommendations in the sections below, and the examples provided in Appendix A. Answer the questions posed in the text for each individual type of change (e.g., performance change, material change) until a decision is made either to submit a new 510(k) or to document the basis for concluding that a new 510(k) is not required. As mentioned above, when making the decision on whether to submit a new 510(k) for changes, the manufacturer's basis for comparison of any changed device should be the device described in the manufacturer s most recently cleared 510(k) for this device, or to their legally marketed preamendments device. Manufacturers are required to submit a new 510(k) when a change (or changes) exceeds the 807.81(a)(3) threshold, "could significantly affect the safety or effectiveness of the device," or constitutes a major change or modification in the intended use of the device. This significant effect could be positive or negative. One must keep in mind that what may on the surface appear to be one discrete change to a device may involve multiple changes of various types. Although this guidance does not specifically discuss manufacturing changes, a manufacturer should consider the impact of all manufacturing changes on device labeling, technology/performance, and/or materials. If the manufacturing change affects any of these three areas, manufacturers should evaluate the impact of the resulting labeling, technology/performance, or material change using the appropriate flowcharts and companion text. In cases with multiple changes, manufacturers should use all applicable flowcharts and explanatory text. Consider the following examples: Example 1: Multiple changes caused by a manufacturing process change A manufacturer decides to change the manufacturing process for a patient-contacting part from a machining process to a stamping process. The use of the stamping process requires a change in the grade of stainless steel and also results in a change of the dimensional tolerances. To evaluate the impact of this change, the manufacturer should use both Sections B (Technology, Engineering, and Performance) and C (Materials). Example 2: Multiple changes related to a change in shelf-life A manufacturer changes one or more materials in a device to improve the shelf-life of the product. The material change also affects some of the performance characteristics, resulting in the need to update the labeling. To evaluate the impact of the change, the manufacturer should use Sections A (Labeling), B (Technology, Engineering, and Performance) and C (Materials) or D (Technology, Engineering, Performance, and Materials Changes for IVD Devices). For those circumstances where the proposed change is not addressed in this guidance or in a device-specific guidance document, manufacturers are encouraged to contact CDRH staff or CBER staff. 9

320 321 322 323 324 325 326 327 328 329 330 331 332 333 334 335 336 337 338 339 340 341 342 343 344 345 346 347 348 Note that the flowchart entries, new 510(k) and documentation, are written in this way only for conciseness. The reader should interpret new 510(k) as a new 510(k) is likely required and documentation as a new 510(k) is likely not required, document your analysis and file it for future reference. Each of the questions listed on the detailed flowcharts are identified by the flowchart letter (A through D) and a sequential number. Those questions on the main spine of the flowcharts relate to major questions to be answered. Subsidiary questions are identified by the flowchart letter, the question number, a decimal point, and another sequential number (e.g., B4.1 is a decision point containing a follow-up question that builds off a determination made in decision point B4). Note that the first question is always whether the change is being made with the intent to significantly improve the safety or effectiveness of the device, for example, in response to a known risk, adverse event, etc. (Figure 1 Main Flowchart). If so, then the change likely could significantly affect safety or effectiveness and a new 510(k) likely must be submitted. This guidance provides a logic scheme that incorporates risk assessment for evaluating specific types of device changes and modifications, and, in instances where it is not possible to provide further specific guidance, refers to Section E, which provides recommendations for how manufacturers should utilize risk management principles to evaluate their own specific changes and modifications. Because 21 CFR 807.81(a)(3)(i) requires a new 510(k) when a change could significantly affect safety or effectiveness, both safety and effectiveness should be considered in evaluating a device s risk profile, as explained in Section E. 10

349 350 351 352 353 354 355 356 357 358 359 360 361 362 363 364 365 366 367 368 369 370 371 372 373 374 375 376 377 378 379 380 381 A. Labeling Changes As noted above, the types of changes are divided into labeling changes, technology, engineering, or performance changes, and materials changes. All labeling changes should be evaluated using a separate logic scheme that concentrates on changes in indications for use for determining whether clearance of a new 510(k) is required. Other labeling changes are more frequently recommended for documentation only. Flowchart A describes the logic scheme to be used when determining when a new 510(k) is required for a labeling change. Changes in device labeling often pose the most difficult questions to be addressed by device manufacturers when deciding when a new 510(k) is required. Frequently, an apparently subtle change in a device s labeling can have a significant impact on the safe and effective use of the device. Confusion often results when discussing the distinction between indications for use and the intended use of the device. For purposes of substantial equivalence, the term intended use means the general purpose of the device or its function, and encompasses the indications for use. 2 The indications for use describe the disease or condition the device will diagnose, treat, prevent, cure or mitigate, including a description of the patient population for which the device is intended. 3 The indications include all the labeled patient uses of the device. The concept of intended use has particular relevance in determining whether a device can be cleared for marketing through the premarket notification (510(k)) process or must be evaluated in a premarket approval application (PMA) or a de novo request for classification under section 513(f)(2) of the FD&C Act. Manufacturers should recognize that, per section 513(i) of the FD&C Act, if a particular labeling change results in a different intended use of the device, the device would not be substantially equivalent and a PMA or a de novo submission would be required to market the device. Rather than referring to intended use as a determinant in deciding when to submit a new 510(k), this guidance identifies several types of labeling changes or modifications that have a major impact on intended use and thus would require the submission of a new 510(k). 4 FDA interprets major changes in intended use to be a type of change that could significantly affect safety or effectiveness. 2 See FDA s guidance, The 510(k) Program: Evaluating Substantial Equivalence in Premarket Notifications (510(k)). 3 Ibid. 4 Labeling changes are not the only type of changes that could result in a major change in intended use. See 21 CFR 801.4. 11

382 383 384 385 386 387 388 389 390 391 392 393 394 395 396 397 Figure 2 - Flowchart A A1. Is it a substantive change in the indications for use? Changes in the indications for use section of labeling raise more Agency concern than any other aspect of labeling. In fact, most changes in this part of the labeling that affect the substance, meaning, or scope of the indications for use referred to here as substantive changes could significantly affect safety or effectiveness and will require the submission of a new 510(k). Changes that clarify the indications without affecting the substance or meaning of the indications usually do not require a new 510(k). In addition, some changes in the indications for use that limit use within the currently cleared indication may occur without the submission of a new 510(k). For example, if a device was cleared for use with three specific indications and the firm decides to market the device for only two of those indications, this change would not likely require submission of a new 510(k). 12

398 399 400 401 402 403 404 405 406 407 408 409 410 411 412 413 414 415 416 417 418 419 420 421 422 423 424 425 426 427 428 429 430 431 432 433 434 435 Common changes to the indications for use that typically could significantly affect safety or effectiveness and therefore usually require submission of a new 510(k) are: (1) Reuse of devices previously labeled single-use only. (2) Changes from prescription to over the counter (OTC). (3) Changes that introduce a new therapeutic or diagnostic claim. (4) Changes to allow device use in a new patient population. (5) Changes to the type of joint, organ, bone, vasculature, or tissue applied to or interacted with. Common changes that likely would not constitute a major change in intended use and would not require a new 510(k) include: (1) Changes to the device name or description that are consistent with the cleared indications for use; and (2) Changes to improve readability or clarity that do not affect the substance of the indications for use. Whether other indication changes require a new 510(k) will be more dependent on the specific device, the original indications for use, and the modified indications for use. To determine whether such types of changes to the indications for use could significantly affect the device s safety or effectiveness, manufacturers should consider how the change affects the device s risk profile. As discussed in Section E, a change that introduces a new risk or significantly modifies an existing risk likely requires a new 510(k). The following are examples of types of indication for use changes that may require a new 510(k), as well as points to consider in determining whether a new 510(k) is required: (1) Changes in use environment. How a change of this type affects a device s risk profile depends on the differences in use environment and environmental specifications. For example, a change from use in a surgical suite to use in a hospital recovery room, both of which will have professional healthcare supervision, may not affect the device s risk profile. Changes from professional use to home use 5 or hospital use to ambulatory transport, however, are more likely to affect the device s risk profile and require a new 510(k) because the different environments have different levels of professional healthcare supervision or user training and offer different 5 A home use medical device is a medical device intended for users in any environment outside of a professional healthcare facility. This includes devices intended for use in both professional healthcare facilities and homes. See FDA s Home Use Devices website for more information: http://www.fda.gov/medicaldevices/productsandmedicalprocedures/homehealthandconsumer/homeusedevi ces/default.htm. 13

436 437 438 439 440 441 442 443 444 445 446 447 448 449 450 451 452 453 454 455 456 457 458 459 460 461 462 463 464 465 466 467 468 469 470 471 472 473 474 475 476 477 478 479 480 environmental challenges, such as presence of other electronic devices that can cause electromagnetic interference, different levels of cleanliness, or shocks and vibrations associated with patient travel or ambulatory use. (2) Changes to enable use of the device by a different user. Similar to changes in use environment, how this type of change affects a device s risk profile depends on the difference in users. Changes between similar types of users, such as changes between a general physician and a specialist may not significantly affect a device s risk profile. Changes that enable unsupervised use by a lay user as opposed to use by a healthcare provider (professional use to lay use or prescription use to over-the-counter use), however, are likely to significantly affect the device s risk profile and require a new 510(k) due to the different levels of user training. (3) Changes in the indications for use to a more specific use than the currently cleared general indication. Manufacturers should carefully consider the potential effects on their device s risk profile in making these changes, as they are among the most difficult to assess. If a change of this type has the potential to expand device use to different users, different use environments, use in or on a different type of joint, organ, bone, vasculature, or tissue, use in different patient populations, or new therapeutic or diagnostic uses, it should be evaluated using the guidance provided above. FDA s Guidance for Industry: General/Specific Intended Use provides information on when a specific indication for use is reasonably included within a general indication for use for purposes of determining substantial equivalence, i.e., whether a 510(k) can be cleared or whether, instead, a PMA or de novo submission is required. The factors discussed therein particularly those discussing the risk and public health impact of an indication change may be helpful to consider in deciding whether to submit a new 510(k) for a change to an existing device, but that guidance should not be used in and of itself to justify that a new 510(k) is not required. The General/Specific guidance is not intended to provide guidance on when a new 510(k) is required for changes to an existing device. (4) Changes in frequency or duration of use. Changes in the frequency or duration of use of a device include changes indicating that a device can or should be used more or less often, changes indicating that a device can perform a task or treat a 14

481 482 483 484 485 486 487 488 489 490 491 492 493 494 495 496 497 498 499 500 501 502 503 504 505 506 507 508 509 510 511 512 513 514 515 516 517 518 519 520 521 522 523 524 condition in or for a different duration of time, or changes from periodic to continuous monitoring. Manufacturers should evaluate the effect such changes could have on the performance of a device, and whether such changes significantly affect the device s risk profile. (5) Changes concerning the compatibility or interoperability of a device with other devices, components, or accessories. An example of such changes would include changes indicating an IVD reagent for use with a new system. To evaluate whether these changes affect the device s risk profile, manufacturers should carefully consider the following factors: Differences between other devices, components, or accessories in previously cleared indications and in the modified indications. Manufacturers should be able to clearly identify and analyze the risks associated with such differences, including whether the change may affect biocompatibility, performance, connectivity, etc. If the change is to indicate compatibility with a type of device, component, or accessory that has not been indicated as compatible previously, that change will likely require a new 510(k). The criticality of the other device, component, or accessory should be factored in; the more critical the other device, component, or accessory is to overall system function, the more likely a labeling change regarding compatibility or interoperability could significantly affect safety or effectiveness. The labeling of the other device, component, or accessory should be considered. If the change is to indicate compatibility or interoperability with another device that is also labeled for use with the subject device or device type, it is less likely that the change introduces a compatibility or interoperability issue that could significantly affect safety or effectiveness. IVD manufacturers should see also FDA s Replacement Reagent and Instrument Family Policy guidance. If the modification is a substantive change in the indications for use, a new 510(k) is likely required. Otherwise, proceed to A2. A2. Does the change add or delete a contraindication? Changes in the labeled contraindications for device use generally could significantly affect safety or effectiveness of a device and should typically be reviewed by the Agency, however, FDA recognizes that, in general, the addition of a contraindication based on new information is important to public health. Because of this, manufacturers are encouraged to add new contraindications to their labeling and to notify existing users 15

525 526 527 528 529 530 531 532 533 534 535 536 537 538 539 540 541 542 543 544 545 546 547 548 549 550 551 552 553 554 555 556 557 558 559 560 561 562 563 564 565 566 567 568 569 of their device as expeditiously as possible whenever a pressing public health need arises. The new labeling should be submitted to FDA as part of a new 510(k) that is prominently labeled change being effected (CBE, in Figure 2- Flowchart A). FDA does not intend to take enforcement action against a device marketed with the modified labeling that is submitted as part of a new CBE 510(k) while the 510(k) is pending. Manufacturers should ensure they are thoroughly familiar with the definition of a contraindication in such situations. Deletion or modification of a contraindication usually requires the submission of a new 510(k) prior to effecting the change, because this type of labeling change typically substantively changes the indications for use. Deletions of contraindications would expand the indications for use. For example, if a physical restraint was contraindicated for use with individuals weighing less than 100 pounds because of established life-threatening and other serious adverse events, and the manufacturer subsequently wishes to remove this contraindication, a new 510(k) is likely required. Similar to changes in indications for use, modifications that clarify or reword a contraindication without affecting the substance of the contraindication would not typically require a new 510(k). If the change adds or deletes a contraindication, a new 510(k) is likely required. Otherwise, proceed to A3. A3. Is it a change in warnings or precautions? In order to facilitate a continuous upgrading in device labeling, manufacturers should monitor device usage and promptly revise the warnings and precautions section(s) based on user experience. Events that precipitate changes of this type may be those reported under the medical device reporting regulation (MDR), 21 CFR Part 803. New 510(k)s for such labeling changes are generally not required, however, manufacturers should first proceed to A5.1 and A5.2 and carefully consider whether the changes could affect the indications for use or the device s risk profile. A4. Does the change affect the instructions for use or other pieces of the labeling? Device labeling may be changed for a multitude of reasons. Many labeling changes result from attempts to clarify labeling. Manufacturers should consider points A5.1 and A5.2, and if the change could affect how the device is used in practice. Labeling changes that provide clarification without changing the meaning of the labeling would generally not result in the need to submit a new 510(k). A5.1 Could the change affect the indications for use? It is important to note that changes to other parts of the labeling, such as the instructions for use, can affect the indications for use even if the indications for use statement itself does not change. Whether a labeling change can affect the indications for use will be device dependent. As mentioned above, changes that could affect the indications for use of a device generally require a new 510(k). 16

570 571 572 573 574 575 576 577 578 579 580 581 582 583 584 585 586 587 588 589 590 591 592 593 594 595 596 597 598 599 600 601 602 603 604 605 606 607 608 609 610 611 612 613 Examples of labeling changes that could affect indications for use include: (1) Adding additional or new instructions on how to interpret diagnostic data from a diagnostic device. (2) Adding a new procedural technique not described in the original labeling. (3) Adding instructions for device use in a different patient population. (4) Adding instructions for device use in a different type of joint, organ, bone, vasculature, or tissue. (5) Changes from single-use to multiple use. If the change affects the indications for use, a new 510(k) is likely required. Otherwise, proceed to A5.2. A5.2 Does a risk assessment of the changed device identify any new risks or significantly modified existing risks? Changes to the labeling can also affect a device s risk profile by affecting the way the device is used. As discussed in Question 1 of the Main Flowchart, if a change to labeling is intended to significantly affect safety or effectiveness by mitigating a new risk or an increased probability or severity of a known risk, that change likely requires a new 510(k), particularly if the new risk or increased risk has resulted in a recall, adverse events, or change in the acceptability of the risk. For labeling changes that are not intended to mitigate risks, but could affect a device s risk profile, manufacturers should consult Section E and consider whether the change creates or significantly modifies risks. As part of that evaluation, manufacturers should consider whether changes to labeling could introduce human factors or usability issues that could significantly affect users understanding of the labeling and use of the device. Changes that significantly affect a device s risk profile likely require a new 510(k). Examples of labeling changes that may affect the device s risk profile include: (1) Use of a product for a duration/frequency that is different than what is described in the labeling of the cleared device. (2) Changing from labeling a device as non-sterile to labeling it as sterile. (3) Changes concerning device compatibility or interoperability with other devices, components, or accessories. See A1, above. Manufacturers should consider the factors discussed there to determine whether these changes will require a new 510(k). If the change significantly affects the device s risk profile, a new 510(k) is likely required. Otherwise, a 510(k) is likely unnecessary for a labeling change, unless otherwise indicated above. 17

614 615 616 617 618 619 620 621 622 623 624 625 626 627 628 629 630 FDA believes that, if manufacturers follow this approach to changes in device labeling, only necessary new 510(k)s (those changes that could significantly impact safety and effectiveness) will be submitted, while the submission of unnecessary new 510(k)s (those that could not significantly affect safety and effectiveness) will be minimized. At the same time, manufacturers should be able to retain the flexibility to improve their labeling to assure safe and effective use of their devices. B. Technology, Engineering, and Performance Changes These types of changes encompass a broad span of design activities, from minor engineering changes in a circuit board layout to a change from electromechanical to microprocessor control of device function. Flowchart B illustrates the decision-making logic scheme for such technology, engineering or performance changes to a device. All changes should be evaluated using this scheme, and then the changes should be verified and/or validated according to the QS requirements, 21 CFR 820.30(i). If the results of the verification and/or validation raise any unexpected issues, the decision of whether a new 510(k) is required should be re-evaluated per B5.4. 18

631 632 633 634 635 636 Figure 3 - Flowchart B B1. Is the device an in vitro diagnostic device? If the device is an IVD, refer to the later section of this guidance which is specific to technology, engineering, and 19

637 638 639 640 641 642 643 644 645 646 647 648 649 650 651 652 653 654 655 656 657 658 659 660 661 662 663 664 665 666 667 668 669 670 671 672 673 674 675 676 677 678 679 680 681 performance changes in IVDs (Section D Technology, Engineering, Performance, and Materials Changes for In Vitro Diagnostic Devices). B2. Is it a control mechanism, operating principle, or energy type change? Control mechanism changes: A control mechanism, for the purpose of this guidance, is the manner by which the actions of a device are directed. Almost all changes in the control mechanism for a device could significantly affect safety and effectiveness. Therefore, such changes will normally require the submission of a new 510(k). This is also true for changes in operating principle as well as for changes in energy type (discussed below). Changes of these types tend to be more revolutionary than evolutionary. One example of a control mechanism change would be a change from analog to digital control of a medical device. While the change to digital control can markedly improve device performance specifications and effectiveness, the integration of a digital control into a previously all-analog system is complex and usually undertaken only as part of a major redesign of a product. Thus, it would be rare that a new 510(k) would not be required. Most often, such changes in control mechanism represent the introduction of a new product line. Other changes in control mechanism of a similar nature would also likely require a new 510(k). An example of such a change would be the change from pneumatic to electronic control of a respiratory care device. Operating principle changes: Similar to a control mechanism change, a change in operating principle would also usually require the submission of a new 510(k). An example of a new operating principle for a device would be changing the image reconstruction algorithm used in a computed tomography x-ray system from simple back projection to a new, more radiation-efficient method. In this case, testing both at the bench and in the clinic would be necessary to support a finding of substantial equivalence for the new device. Another example would be a change in a water droplet dispersal method used by a respiratory gas humidifier from piezoelectric material to a wick and fan method. The two mechanisms use the same design principle, but apply it in different ways. The differences between the two could significantly affect safety and effectiveness. Such changes may also be accompanied by significant labeling changes and, sometimes, by a need for operator retraining to ensure continued safe and effective operation. Energy type changes: The submission of a new 510(k) will usually be required for energy type changes. These changes include both energy output and input changes. A change from emitting microwave energy to radiofrequency (RF) energy would be an example of an energy output change; this type of change would likely be part of a 20

682 683 684 685 686 687 688 689 690 691 692 693 694 695 696 697 698 699 700 701 702 703 704 705 706 707 708 709 710 711 712 713 714 715 716 717 718 719 720 721 722 723 724 725 726 significant redesign. An example of an energy type input change is a modification from AC to battery power; this type of change is usually part of a redesign to provide a portable device that can be used under different environmental conditions than the original device. Such a change would normally be accompanied by significant labeling changes, including a new or expanded indication for use. Note that this type of change does not include a change in voltage, such as from 3V to 9V operation or a change between different types of batteries, such as from NiCad to lead acid storage batteries. Such changes should be considered changes in performance specifications or device design, as discussed at decision point B5. B3. Is it a change in sterilization, cleaning, or disinfection? Changes in sterilization, cleaning, or disinfection should be carefully assessed. If there is a change of this type, proceed to B3.1. B3.1 Is it a change to an established category B or novel sterilization method, does the change lower the sterility assurance level, or is it a change to how the device is provided? Changes from established category A sterilization methods to established category B or novel sterilization methods generally require a new 510(k). Changes from one established category A method to another established category A method, or from an established category B or novel method to an established category A method, should be evaluated under B3.2. See FDA s guidance Submission and Review of Sterility Information in Premarket Notification (510(k)) Submissions for Devices Labeled as Sterile for a discussion of sterilization methods. If the sterility assurance level (SAL) is lowered, manufacturers should consider whether device safety or effectiveness may be compromised by the new level. In general, reductions in SAL require new 510(k) submissions unless the SAL remains better than 10-6. Note that changes to cleaning and disinfection processes for reprocessed devices can also affect the bioburden levels on a device, which may invalidate subsequent processing steps such as sterilization; manufacturers should carefully consider whether these changes could significantly affect the safety or effectiveness of the device. It is likely that changes to reprocessing procedures for devices listed in Appendix E of FDA s guidance, Reprocessing Medical Devices in Health Care Settings: Validation Methods and Labeling, could significantly affect safety or effectiveness. FDA has identified the devices there as a subset of medical devices that pose a greater likelihood of microbial transmission and represent a high risk of infection (subclinical or clinical) if they are not adequately reprocessed. Some changes to how a device is provided to the user or patient could also significantly affect safety or effectiveness. For the purposes of this question, how a device is provided refers to whether the device is provided sterile or non-sterile, and to whether the device is provided for (1) single-patient, single-use, (2) single-patient, multi-use, or (3) multi-patient, multi-use. If a device is changed from (1) to (2), (1) to (3), or (2) to (3), i.e., provided for more patients and/or more uses, a 510(k) is likely 21

727 728 729 730 731 732 733 734 735 736 737 738 739 740 741 742 743 744 745 746 747 748 749 750 751 752 753 754 755 756 757 758 759 760 761 762 763 764 765 766 767 768 769 770 771 required. However, the reverse would not be true; it would be unlikely that a change from (3) to (2), (3) to (1), or (2) to (1) could significantly affect safety or effectiveness and therefore would not likely require a new 510(k). In addition, if a device that was originally provided sterile is modified to be provided non-sterile either to be sterilized by the user or to be used without sterilization a new 510(k) is likely required. A new 510(k) is also likely required if a device originally provided non-sterile is modified to be provided sterile. If the answer to this question is yes, a new 510(k) is likely required. If the answer is no, proceed to B3.2. B3.2 Could the change significantly affect the performance or biocompatibility of the device? Changes in the method of sterilization, cleaning, or disinfection have the potential to change material or performance characteristics of a device. This is particularly true of the properties of polymeric materials or surface coatings. When manufacturers make changes in sterilization, cleaning, or disinfection methods, they should consider whether the properties or specifications of the device could be significantly affected. To determine whether the sterilization, cleaning, or disinfection change could significantly affect device performance, the manufacturer should consider known information on the sterilization, cleaning or disinfection method, its parameters, and the material being sterilized, cleaned, or disinfected, and determine if there are any new or significantly modified risks associated with using the proposed method and its parameters with the device s materials of construction. If there are new or significantly modified risks (see Section E), this likely indicates that the change could significantly affect the device s safety or effectiveness. Note also that if verification and/or validation of the new methods show any unexpected results, manufacturers should re-evaluate whether a new 510(k) is required (see B5.4). Sterilization, cleaning, or disinfection changes may also affect the biocompatibility of a device. For instance, changes to an ethylene oxide sterilization process may leave increased ethylene oxide residuals on the device surface, or changes to a cleaning process may incorporate chemicals that are inappropriate for use with a patientcontacting device. Manufacturers should consider whether sterilization, cleaning, or disinfection changes could significantly affect the biocompatibility of their device. If a manufacturer determines their cleaning, disinfection, or sterilization change could significantly affect the performance or biocompatibility of the device, a new 510(k) is likely required. Otherwise, it is unlikely a 510(k) is required as a result of this type of change. B4. Is there a change in packaging or expiration dating? If yes, proceed to B4.1. B4.1 Is the same method or protocol, as described in a previously cleared 510(k), used to support the change? Generally, changes in device packaging or changes in the 22

772 773 774 775 776 777 778 779 780 781 782 783 784 785 786 787 788 789 790 791 792 793 794 795 796 797 798 799 800 801 802 803 804 805 806 807 808 809 810 811 812 expiration date for use of a device do not require a new 510(k). FDA relies on the QS regulation (21 CFR Part 820) to reasonably assure the safety and effectiveness of devices with these types of changes. This is true whether or not the manufacturer applies an expiration date because of package integrity considerations, e.g., sterility, or because of a finite shelf-life of the device. However, where methods or protocols that are not described in a previously cleared 510(k) are used to support new package integrity or shelf-life claims, 3a new 510(k) is likely required. B5. Is it any other change in design (e.g., dimensions, performance specifications, wireless communication, components or accessories, or the patient/user interface)? These types of design or engineering changes encompass everything from the routine specification changes necessary to maintain or improve device performance as a result of feedback from users, field or plant personnel, etc., up to and including significant product redesign. The bullets below highlight some, but not all, of these changes, and provide points to consider for each type of change. Dimension changes: In determining whether a new 510(k) is required for these types of changes, per B5.1-B5.4, the manufacturer should consider not only the size of the dimension or dimensional specification change, but the criticality of the modified dimension. The more critical the dimensions being modified are to the safe and effective operation of the device, the more likely it is that the change could significantly affect safety or effectiveness. For instance, a 1 mm change to the diameter of a working channel of an endoscope is more likely to significantly affect safety or effectiveness than a 1 mm change to the length of an endoscope. If a modified dimension is within a range of dimensions previously cleared for the original device, a new 510(k) would not typically be required. For instance, if the original device was cleared with two models that were 2 and 4 mm in diameter, and the modified device of the same length has a diameter of 3 mm, a new 510(k) is likely not required for this change. Device performance changes: This category covers a broad range of changes. As discussed in the Main Flowchart, Question 1, changes that are intended to significantly affect device safety or effectiveness likely require a new 510(k). Changes that are not intended to affect device safety or effectiveness should be considered per B5.1-B5.4. Wireless communication changes: Changes to device communication between device components or between the modified device and other products, particularly from wired to wireless, may change a device s risk profile by introducing or modifying risks regarding data transmission or cybersecurity. 6 6 See FDA s webpage on cybersecurity in medical devices, http://www.fda.gov/medicaldevices/productsandmedicalprocedures/connectedhealth/ucm373213.htm. 23

813 814 815 816 817 818 819 820 821 822 823 824 825 826 827 828 829 830 831 832 833 834 835 836 837 838 839 840 841 842 843 844 845 846 847 848 849 850 851 852 853 854 855 856 857 Changes to employ wireless communication in devices where it was previously not used are likely to significantly affect safety or effectiveness and likely require a new 510(k). This is particularly true when wireless communication is used to control device operations. When evaluating other changes, including a change to a different wireless communication protocol, the factors in B5.1-B5.4 should be taken into account in determining whether a new 510(k) is required. Components or accessories: Changes to components or accessories could, in some cases, significantly affect the safety or effectiveness of the device as a whole. In B5.1, manufacturers should consider whether changes to the device or any of its components or accessories affect the use of other components or accessories, or if changes to a component or accessory could lead a device to be used in a new way. In B5.2, manufacturers should consider whether changes to the device or any of its components or accessories could disrupt compatibility between the device and its components or its accessories, and whether these changes could lead to a significant change in the device s risk profile. Changes in the human factors of the patient or user interface: A device user interface includes all points of interaction between the product and the user, including elements such as displays, controls, and packaging. User interface changes refer to changes in the way in which a patient or user interacts with a device, including, for example, the way in which the device presents alarms to the user, the layout of the control panel, the mode of presentation of information to the user or patient, and the way in which the device physically interacts with the user and/or patient (e.g., the way in which a CPAP mask attaches to a patient s face, or the way a surgical instrument is designed to fit in a surgeon s hand). Note that this type of change includes changes that modify a user workflow (tasks performed by a user in order to complete their work). Manufacturers should consider the risk impact of changes in user workflow; for example, providing new information to the user or modifying the manner in which information is presented may impact user comprehension. In addition, changing the layout of device controls may impact device use differently in different use scenarios. For more information on applying human factors in medical devices, see FDA s guidance Applying Human Factors and Usability Engineering to Optimize Medical Device Design. Changes intended only to increase user or patient comfort when interacting with the device may be particularly difficult to evaluate. These changes will typically not require a new 510(k), but some changes made for the comfort of the user or patient could significantly affect safety or effectiveness. For example, if a surgical handpiece is redesigned to move a motor closer to the surgeon s hand or the surgical site, any heating of the motor will be more likely to affect the surgeon or patient and could result in burns. Manufacturers should evaluate changes to a user interface and whether they significantly affect safety or effectiveness in answering B5.1-B5.4. 24

858 859 860 861 862 863 864 865 866 867 868 869 870 871 872 873 874 875 876 877 878 879 880 881 882 883 884 885 886 887 888 889 890 891 892 893 894 895 896 897 898 899 900 Changes in design should be considered, along with the above bulleted points, in answering B5.1-B5.4. B5.1 Does the change significantly affect the use of the device? As with a labeling change, if a design change significantly affects how a device may be used, a new 510(k) is likely required. Manufacturers should consider whether the change increases the likelihood that the device will be used by a broader or different group of users who have less training regarding safe and effective use of the device (e.g., lay users instead of clinicians, or general practitioners instead of surgeons) and whether that change affects the risk profile of the device. If the change significantly affects the risk profile (see Section E), a new 510(k) is likely required. Manufacturers should also consider whether the change increases the likelihood that the device will be used in a new environment, and whether the new environment affects the risk profile of the device. If the change facilitates use in a completely different environment (e.g., from hospital to home use, or from hospital to ambulance transport), this typically will introduce new or significantly modified risks and will likely require a new 510(k). If the change facilitates use only in similar environments, the risk profile of a device may also be changed, but this is less likely to require a new 510(k). In deciding whether a change that allows use of the device in a new environment could significantly affect the safety or effectiveness of the device, manufacturers should consider differences in environmental specifications such as: (1) Temperatures and humidity that might affect device operation; (2) Noises that might drown out the sound of auditory alarms; (3) Exposure to water, soils, or light that might affect device operation; (4) Presence of other devices or equipment that may cause electromagnetic interference; and (5) Possible use in magnetic resonance imaging (MRI). If the change introduces new or significantly modified risks, a new 510(k) is likely required. If the change significantly affects use of the device, a new 510(k) is likely required. If it does not, proceed to B5.2. B5.2 Does a risk assessment of the changed device identify any new risks or significantly modified existing risks? As discussed in the Guiding Principles and Section E, the manufacturer should conduct a risk assessment for any modified device. New risks, changes to the acceptability of previously identified risks, or changes to device features that may be critical to the device s safe or effective operation will likely require new 510(k)s. 25

901 902 903 904 905 906 907 908 909 910 911 912 913 914 915 916 917 918 919 920 921 922 923 924 925 926 927 928 929 930 931 932 933 934 935 936 937 938 939 940 941 942 943 944 Manufacturers should carefully consider whether changing one aspect or feature of a device s design might affect a seemingly unrelated aspect or feature. For instance, a dimensional or component change may affect the ability to reprocess a device or the ability to regulate the temperature of an electronic device. Manufacturers should evaluate these impacts of the change as part of their risk assessment. If a risk assessment does not identify any new risks or significantly modified existing risks or effectiveness issues per Section E, proceed to B5.3. B5.3 Are clinical data necessary to evaluate safety or effectiveness for purposes of design validation? Whenever a manufacturer recognizes that clinical data are needed because bench testing or simulations are not sufficient to assess the impact of the change on safety or effectiveness to validate the design change, a new 510(k) is likely required. For the purposes of this question, clinical data does not include data not used for design validation, such as user or patient preference testing. If clinical data are unnecessary to evaluate safety and effectiveness for purposes of design validation, proceed to B5.4. B5.4 Do design verification and/or validation activities produce any unexpected issues of safety or effectiveness? All changes to device design should undergo some level of design verification and/or validation or evaluation to ensure that the device continues to perform as intended. See 21 CFR 820.30. As discussed in the Guiding Principles, manufacturers should make an initial risk-based assessment of whether a change requires a new 510(k). If the manufacturer determines after an initial assessment that a new 510(k) is not required, the manufacturer should conduct routine verification and validation activities to ensure that no new issues of safety or effectiveness are raised. If successful application of routine verification and validation activities confirms the initial assessment, manufacturers should proceed with the design change and document their assessment. Occasionally, routine verification and validation activities may either produce unexpected results or otherwise prove to be inadequate to verify and/or validate the modified design. In such instances, the manufacturer likely is required to submit a new 510(k). If a manufacturer encounters unexpected results performing routine verification and validation activities for example, the device does not perform as expected, prespecified acceptance criteria are not met, or testing demonstrates unexpected safety or effectiveness issues the manufacturer should analyze the results carefully. The initial risk assessment should be re-evaluated, and if changes to that assessment are necessary, the manufacturer should re-evaluate whether the device change could significantly affect safety or effectiveness. If different verification and/or validation test methods or acceptance criteria are necessary to produce the expected results, it is 26

945 946 947 948 949 950 951 952 953 954 955 956 957 958 959 960 961 962 963 964 965 966 967 968 969 970 971 972 973 974 975 976 977 978 979 980 981 982 983 984 985 986 likely that the change could significantly affect safety or effectiveness and thus a new 510(k) is likely required. If the manufacturer determines prior to conducting verification and validation activities that routine verification and validation activities are insufficient and the design change necessitates a different verification and/or validation scheme or new acceptance criteria, a new 510(k) is likely required. This does not mean that manufacturers should not update test methods and acceptance criteria for verification and validation activities in accordance with advances in science or relevant voluntary consensus standards, but if the design change drives the need for a new testing scheme or acceptance criteria (as opposed to advances in science or standards), it is likely that the design change could significantly affect safety or effectiveness. If the initial assessment determines a new 510(k) is not required, and verification and validation activities are substantially unchanged (i.e., use the same test methods and same acceptance criteria) and successful, then proceed to Section C. For example, in order to better accommodate connection of a urinary drainage (Foley) catheter to a collection apparatus, the manufacturer increases the length of the catheter by several millimeters. The new length is outside of previously cleared lengths for this device, however, the length change is not far outside cleared lengths. Based on its risk assessment, the manufacturer does not expect the length change will create any new risks or significantly affect existing risks. The manufacturer therefore determines that the length change could not significantly affect the device s safety or effectiveness, and does not require a new 510(k). The manufacturer subsequently conducts design control activities, and verifies that the catheter functions safely and effectively, as predicted, with no unexpected results. The manufacturer documents these efforts and proceeds to production. On the other hand, a manufacturer of monitoring devices wants to use a more sensitive comparator circuit, and makes other design changes to accommodate the more sensitive component. The design change is similarly evaluated in an initial risk assessment based on models, calculations, etc., and a decision is made that the change could not significantly affect the device s safety or effectiveness, and therefore the changes do not require a new 510(k). However, as part of routine verification and validation activities, tests with a simulator produce unexpected results, and additional work is necessary to understand how and why this outcome occurred. The manufacturer should carefully assess these results and whether new issues of safety or effectiveness have been uncovered. C. Materials Changes 27

987 988 989 990 991 992 993 Firms making changes to the materials from which their device is manufactured should also consider the other types of changes discussed above and their impact on the decision regarding a new 510(k). For example, a material change, as discussed below, might also lead to a change in the labeling of the device (e.g., the removal of a contraindication or the addition of a new warning), or a change in specifications (e.g., a reduction in the strength of the device). These collateral changes should be considered in addition to the logic scheme described in this section. 994 995 996 997 Figure 4 - Flowchart C 28

998 999 1000 1001 1002 1003 1004 1005 1006 1007 1008 1009 1010 1011 1012 1013 1014 1015 1016 1017 1018 1019 1020 1021 1022 1023 1024 1025 1026 1027 1028 1029 1030 1031 1032 1033 1034 1035 1036 1037 1038 1039 1040 1041 1042 C1. Is the device an in vitro diagnostic device? If the device is an IVD, refer to the later section of this guidance which is specific to materials changes in IVDs (Section D Technology, Engineering, Performance, and Materials Changes for In Vitro Diagnostic Devices). C2. Is this a change in material type, material formulation, chemical composition, or the material s processing? If there is any change in material type, formulation, or chemical composition, the answer to this question should be yes. Additionally, if there is any change in supplier or manufacturer material processing or finishing steps, the answer should also be yes. The biocompatibility and physical properties of a finished device depend not only on the materials, but also on the processing of the materials, manufacturing methods (including the sterilization process), and the manufacturing residuals that may be present on the finished device. Changes of this type should be further evaluated for their potential impact on safety and effectiveness. The subsequent questions, such as C4 and C4.1, address whether the change is significant. Many material changes result from material supplier changes, including changes made by a material supplier, or changes from one supplier to another. When these types of changes occur, the manufacturer should utilize their quality system process to analyze the material and determine the extent of the change made, as this analysis might impact answers to subsequent questions. If there is a change in material type, material formulation, chemical composition, or the material s processing as described above, proceed to C3. Otherwise it is unlikely a new 510(k) is required as a result of a materials change. C3. Will the changed material directly or indirectly contact body tissues or fluids? Both direct and indirect patient and user contact should be considered in answering this question. Direct contact is when a material touches any tissue or bodily substance of a patient or user while the material is still in or on the patient or user. Indirect contact is when a material has the potential to come into contact with any tissue or bodily substance through some intervening material (such as a liquid or gas) by first coming in contact with the intervening material, which subsequently comes in contact with the patient tissue or bodily substance. For example, materials in a catheter hub (the part of the catheter which is external to the patient) can contact the patient indirectly if fluids or drugs are infused through the hub and directly into the patient. While most implant materials contact patients, there are some exceptions. For example, the internal contents of spinal cord stimulators are not patient-contacting; they are hermetically sealed so that there is no material transfer, fluid transfer, or leeching out of any material internal to the device. If the changed material directly or indirectly contacts body tissues or fluids, proceed to C4. If the changed material does not contact body tissues or fluids, proceed to C5. 29

1043 1044 1045 1046 1047 1048 1049 1050 1051 1052 1053 1054 1055 1056 1057 1058 1059 1060 1061 1062 1063 1064 1065 1066 1067 1068 1069 1070 1071 1072 1073 1074 1075 1076 1077 1078 1079 1080 1081 1082 1083 1084 1085 1086 C4. Does a risk assessment identify any new or increased biocompatibility concerns? Manufacturers should conduct a risk assessment, which may include an assessment of the device s toxicological and physical properties, of any changed materials that may contact the patient or user to determine if there are any new or increased biocompatibility concerns. An example of a new concern would be a material change that requires a new type of biocompatibility test, such as an implantation test, that was not required for the original device. An example of an increased concern would be where a new chemical component added to a material requires a genotoxicity analysis of that component (because, for instance, the particular component is noted in the literature as potentially genotoxic), but the original device already required a genotoxicity analysis. ISO 10993-1, Biological Evaluation of Medical Devices Part 1: Evaluation and Testing Within a Risk Management Process may be useful in this assessment. The answer to C4 may be no if a knowledgeable individual reviews the differences in chemical composition or physical properties and determines that the change is minor enough that there is no new concern about biocompatibility. See FDA s Use of International Standard ISO-10993, Biological Evaluation of Medical Devices Part 1: Evaluation and Testing, for further information on how to review such differences. A supporting toxicological assessment can be based on an analysis of the chemical formulations or the results of chemical characterization tests if the detailed formulation is not available (i.e., when the material is provided by a supplier and the formulation is proprietary). If, however, this analysis identifies new chemical entities or other properties that are either novel or have the potential to generate adverse biocompatibility responses, such as genotoxicity, a new 510(k) may be required. If a risk assessment identifies any new or increased biocompatibility risks, consider the questions in C4.1. If no new or increased biocompatibility risks are identified, proceed to C5. C4.1 Has the manufacturer used the same material in a similar legally marketed device? Manufacturers who have identified possible biocompatibility concerns in their risk assessment (C4) should consider whether they have used the same material, in its final, finished state, in another one of its own legally marketed devices that has been cleared or approved by the FDA. If the manufacturer has used the same material in a similar device that has been cleared or approved by the FDA (this would typically involve a biocompatibility evaluation), and there is no postmarket evidence of biocompatibility issues with the device, that may provide evidence that the material will be biocompatible in its new application in the changed device as well and the manufacturer can answer yes to this question. 30

1087 1088 1089 1090 1091 1092 1093 1094 1095 1096 1097 1098 1099 1100 1101 1102 1103 1104 1105 1106 1107 1108 1109 1110 1111 1112 1113 1114 1115 1116 1117 1118 1119 1120 1121 1122 1123 1124 1125 1126 1127 1128 It is important to note that in order to answer yes to this question, the material in question should have the same formulation or chemical composition and be subjected to the same processing, including sterilization (i.e., the comparison should be between materials as they are applied in the final finished device, not between raw materials). In addition, the size and geometry of the changed device or component should not affect the curing of the polymer or result in more material in the new device or component. The previously cleared or approved device should have the same or a more risky type of contact and the same or a longer duration of contact. For example, if a manufacturer intends to use a new material in a limited exposure application (<24 hours), and the manufacturer has used that same material in a cleared or approved device for prolonged exposure (24 hours to 30 days), then it is unlikely that a new 510(k) will be required for this change. If the modified device is intended to have a riskier category of contact (e.g., mucosal membrane contact is riskier than contact with intact skin, and blood contact is riskier than tissue/bone contact) or a longer duration of contact, then the manufacturer should answer no to this question. Contact may be either direct or indirect. Manufacturers should not compare their changed material to materials in other manufacturers legally marketed devices, unless the exact formulation and processing of the device, which may affect the safety and effectiveness of the final finished product, can be verified. If the manufacturer has used the same material in a similar legally marketed device, proceed to C5 to determine if the material change could affect device performance. If the manufacturer has not used the same material in a similar legally marketed device, a new 510(k) is likely required. C5. Could the change affect the device s performance specifications? Manufacturers should consider whether the material change could affect the performance of the device by affecting its strength, hardness, etc. Manufacturers should also consider whether the new material could be affected by any labeled cleaning, disinfection, or sterilization process of the device. If the answer to this question is yes, manufacturers should proceed to B5 above and consider whether the change could significantly affect the safety or effectiveness of the device. If the change could not affect the device s performance specifications, it is unlikely the change could significantly affect safety or effectiveness, and the manufacturer should document the change. D. Technology, Engineering, Performance, and Materials Changes for In Vitro Diagnostic Devices 31

1129 1130 1131 1132 1133 1134 1135 1136 1137 Firms making technology, engineering, performance, or materials changes to their IVD should also consider the other types of changes discussed above in Section A, Labeling Changes, and their impact on the decision regarding submission of a new 510(k). For example, a material change, as discussed below, might also be considered a design change and/or might engender a change in the labeling of a device (e.g., the removal of a contraindication, addition of a new warning, or a change in the measuring range). These collateral changes should be considered also when applying the logic scheme described in this section. From B1/C1 D1 Does the change alter the operating principle of the IVD? Yes Reminder: Flowcharts are provided as a visual aid, but do not capture all necessary considerations. Refer to accompanying text when using this flowchart. No D2 Is the change identified in a device-specific guidance or classification regulation? Yes Yes No New 510(k) Refer to Section E as directed by the text for additional recommendations on use of risk assessment. D3 Does a risk assessment of the changed device identify any new risks or significantly modified existing risks? Yes No 1138 1139 1140 1141 1142 1143 1144 1145 Documentation No D4 Do design verification and validation activities produce any unexpected issues of safety or effectiveness? Figure 5 - Flowchart D D1. Does the change alter the operating principle of the IVD? In most cases, a technology, engineering, performance, or material change that alters the operating principle of an IVD could significantly affect safety and effectiveness, in which case a new 510(k) is required (21 CFR 807.81(a)(3)(i)). Changes in Yes 32